Proteogenomic insights into the biology and treatment of pan-melanoma.

Melanoma is one of the most prevalent skin cancers, with high metastatic rates and poor prognosis. Understanding its molecular pathogenesis is crucial for improving its diagnosis and treatment. Integrated analysis of multi-omics data from 207 treatment-naïve melanomas (primary-cutaneous-melanomas (CM, n = 28), primary-acral-melanomas (AM, n = 81), primary-mucosal-melanomas (MM, n = 28), metastatic-melanomas (n = 27), and nevi (n = 43)) provides insights into melanoma biology. Multivariate analysis reveals that PRKDC amplification is a prognostic molecule for melanomas. Further proteogenomic analysis combined with functional experiments reveals that the cis-effect of PRKDC amplification may lead to tumor proliferation through the activation of DNA repair and folate metabolism pathways. Proteome-based stratification of primary melanomas defines three prognosis-related subtypes, namely, the ECM subtype, angiogenesis subtype (with a high metastasis rate), and cell proliferation subtype, which provides an essential framework for the utilization of specific targeted therapies for particular melanoma subtypes. The immune classification identifies three immune subtypes. Further analysis combined with an independent anti-PD-1 treatment cohort reveals that upregulation of the MAPK7-NFKB signaling pathway may facilitate T-cell recruitment and increase the sensitivity of patients to immunotherapy. In contrast, PRKDC may reduce the sensitivity of melanoma patients to immunotherapy by promoting DNA repair in melanoma cells. These results emphasize the clinical value of multi-omics data and have the potential to improve the understanding of melanoma treatment.

PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma.

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.

LncRNA DYNLRB2-AS1 promotes gemcitabine resistance of nasopharyngeal carcinoma by inhibiting the ubiquitination degradation of DHX9 protein.

Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.

Approaches to selective and potent inhibition of glioblastoma by vanadyl complexes: Inducing mitotic catastrophe and methuosis.

Drug resistance has been a major problem for cancer chemotherapy, especially for glioblastoma multiforme that is aggressive, heterogeneous and recurrent with <3% of a five-year survival and limited methods of clinical treatment. To overcome the problem, great efforts have recently been put in searching for agents inducing death of tumor cells via various non-apoptotic pathways. In the present work, we report for the first time that vanadyl complexes, i.e. bis(acetylacetonato)oxidovanadium (IV) (VO(acac)2), can cause mitotic catastrophe and methuotic death featured by catastrophic macropinocytic vacuole accumulation particularly in glioblastoma cells (GCs). Hence, VO(acac)2 strongly suppressed growth of GCs with both in vitro (IC50 = 4-6 µM) and in vivo models, and is much more potent than the current standard-of-care drug Temozolomide. The selective index is as high as ∼10 or more on GCs over normal neural cells. Importantly, GCs respond well to vanadium treatment regardless whether they are carrying IDH1 wild type gene that causes drug resistance. VO(acac)2 may induce methuosis via the Rac-Mitogen-activated protein kinase kinase 4 (MKK4)-c-Jun N-terminal kinase (JNK) signaling pathway. Furthermore, VO(acac)2-induced methuosis is not through a immunogenicity mechanism, making vanadyl complexes safe for interventional therapy. Overall, our results may encourage development of novel vanadium complexes promising for treatment of neural malignant tumor cells.

ECM stiffness affects cargo sorting into MSC-EVs to regulate their secretion and uptake behaviors.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have garnered extensive attention as natural product-based nanomedicines and potential drug delivery vehicles. However, the specific mechanism for regulating MSC-EVs secretion and delivery remains unclear. Here, we demonstrate that extracellular matrix (ECM) stiffness regulates the secretion and delivery of EVs by affecting MSCs' cargo sorting mechanically. Using multi-omics analysis, we found that a decrease in ECM stiffness impeded the sorting of vesicular transport-related proteins and autophagy-related lipids into MSC-EVs, impairing their secretion and subsequent uptake by macrophages. Hence, MSC-EVs with different secretion and uptake behaviors can be produced by changing the stiffness of culture substrates. This study provides new insights into MSC-EV biology and establishes a connection between MSC-EV behaviors and ECM from a biophysical perspective, providing a basis for the rational design of biomedical materials.

Study on Fatigue Life of Aluminum Alloy 6061-T6 Based on Random Defect Characteristics.

A certain number of hole-like defects will occur in aluminum alloys under cyclic loading. The internal holes will reduce the strength of the material and cause stress concentration, which will aggravate the development of fatigue damage. A classification method of defect features based on X-ray CT damage data is proposed. The random hole distribution model is established through the linear congruence method and the region division method. The hole parameter is introduced as the intermediate variable of the 3D reconstruction model of internal defects. In the mesoscopic stage, the function relationship between the distribution of random holes and the fatigue life is established based on the coupling relationship between the number and proportion of pores and the fatigue life. In the macroscopic stage, the relationship between the random holes and the macroscopic crack growth life is established by taking the crack length as the damage variable. The crack propagation rate decreased with the increase in the number of holes. The prediction model of the whole life stage is established using the life function from microcrack initiation to macroscopic crack propagation. Finally, the validity of the whole stage fatigue life prediction model is demonstrated through the comparison and verification of experiments, which provides a certain engineering value for the life estimation of 6061-T6 aluminum alloy materials.

Clinical Response of Advanced Lung Adenocarcinoma with Class III BRAF G466V Missense Mutation to Dabrafenib and Trametinib: A Case Report.

Aim: BRAF is a pivotal driver gene in cancer development. Based on this, the combination of dabrafenib and trametinib was approved for treating NSCLC patients with BRAFV600E mutations. However, the majority of BRAF mutations in lung cancer are non-V600E variants, particularly class III mutants, which currently lack targeted therapeutic options and result in unfavorable clinical outcomes. Case Presentation: We present a case of advanced lung adenocarcinoma with a class III BRAFG466V mutation. The patient experienced significant pleural and pericardial effusion, leading to chest tightness and an inability to lie flat. Severe pain and limited mobility from lumbar destruction seriously affected the patient's quality of life. Due to the patient's intolerance to chemotherapy, dabrafenib and trametinib combination therapy was chosen. After three months of targeted therapy, the patient's overall condition significantly improved, enabling self-care, and achieving partial response (PR) as an indicator of treatment efficacy. Conclusion: The combination therapy of dabrafenib and trametinib demonstrates remarkable clinical benefits for lung adenocarcinoma patients with the BRAFG466V mutation. Targeted therapy should be considered for patients with BRAF class III mutations, especially those in poor general condition and may not tolerate chemotherapy.

Diagnostic value of 18F-PSMA-1007 PET/CT for predicting the pathological grade of prostate cancer.

This study was designed to evaluate the diagnostic efficacy of relevant parameters of 18F-prostate-specific membrane antigen (PSMA)-1007 PET/CT in predicting the pathological grade of primary prostate cancer. Briefly, a prospective analysis was performed on 53 patients diagnosed with prostate cancer by systematic puncture biopsy, followed by 18F-PSMA-1007 PET/CT examination prior to treatment within 10 d. The patients were grouped in accordance with the Gleason grading system revised by the International Association of Urology Pathology (ISUP). They were divided into high-grade group (ISUP 4-5 group) and low-grade group (ISUP 1-3 group). The differences in maximum standardized uptake value (SUVmax), tumor-to-background ratio (TBR), intraprostatic PSMA-derived tumor volume (iPSMA-TV), and intraprostatic total lesion PSMA (iTL-PSMA) between the high- and low-grade group were statistically significant (p < .001). No significant difference was found for mean standardized uptake value (SUVmean) between the high- and low-grade groups (Z = -1.131, p = .258). Besides, binary multivariate logistic regression analysis showed that only iPSMA-TV and iTL-PSMA were independent predictors of the pathological grading, for which the odds ratios were 18.821 [95% confidence interval (CI): 2.040-173.614, p = .010] and 0.758 (95% CI: 0.613-0.938, p = .011), respectively. The area under the ROC of this regression model was 0.983 (95% CI: 0.958-1.00, p < .001). Only iTL-PSMA was a significant parameter for distinguishing ISUP-4 and ISUP-5 groups (Z = -2.043, p = .041). In a nutshell, 18F-PSMA-1007 PET/CT has good application value in predicting the histopathological grade of primary prostate cancer. Three-dimensional volume metabolism parameters iPSMA-TV and iTL-PSMA were found to be independent predictors for pathological grade.

Predictors and prevalence of COVID-19 vaccination in patients with focal epilepsy following resection surgery.

BACKGROUND AND PURPOSE: In light of the ongoing COVID-19 pandemic, vaccination has emerged as the primary and most effective solution. The aim of this study was to examine compliance rates of vaccination and explore the factors that predict vaccine uptake among patients with epilepsy (PWE) who have undergone resection surgery. METHOD: To examine the variations in vaccination coverage, safety concerns, and factors influencing vaccination hesitancy among PWE who have undergone resection surgery, this study recruited patients with at least one-year follow-up. We utilized questionnaires to gather clinical characteristics and obtain information regarding COVID-19 vaccines. RESULTS: Among the 303 patients included in the study, a majority of 229 (75.58%) achieved a seizure-free outcome (Engel Ia). Of these patients, 178 (58.75%) received at least one dose of COVID-19 vaccine, and the vaccination rate has remained relatively consistent over the past six months. Nearly 94.95% of those who received the vaccine completed the full vaccination regimen, with the majority (n = 174, 97.75%) opting for an inactivated vaccine. Only three patients reported side effects unrelated to epilepsy, and one patient experienced a worsening of typical aura seizures within one month after vaccination. Notably, significant positive associations were observed between COVID-19 vaccine acceptance and adulthood (age 18 years or older) (OR = 1.820, 95% CI = 1.018-3.252, p = 0.043) as well as achieving a seizure-free outcome (OR = 2.823, 95% CI = 1.619-4.921, p < 0.001). Regarding the unvaccinated patients, approximately one-fifth expressed willingness to receive a future COVID-19 vaccine, while the remainder were hesitant (41.60%) or unsure (39.20%) about vaccination. These reservations mainly stemmed from concerns about the potential worsening of seizures and vaccine safety. CONCLUSIONS: Inactivated vaccines can be considered safe for individuals with epilepsy who have undergone resection surgery. The likelihood of being vaccinated was found to be comparatively higher among the cohort with seizure-free status or adults. To promote COVID-19 vaccination among children, it is crucial to implement comprehensive education and public awareness campaigns that emphasize the safety of vaccines. These efforts will help encourage widespread acceptance of vaccination and ensure the well-being of individuals with epilepsy.

[Expressions and Clinical Significance of Notch1 and Hes1 in Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To investigate the expressions of Notch1 and Hes1 in diffuse large B-cell lymphoma (DLBCL), and their correlations with clinical features. METHODS: Immunohistochemistry (IHC) was performed on DLBCL samples (54 cases) and lymphadenitis tissues (20 cases) to evaluate the expressions of Notch1 and Hes1, and analyze their correlations with clinical characteristics of patients. Based on Oncomine database, the expressions of Notch1 and Hes1 mRNA and DNA were also explored. RESULTS: IHC result showed that the positive expression rates of Notch1 and Hes1 in DLBCL patients were significantly higher than those in the control group (P <0.05). In DLBCL patients, the expression of Notch1 was closely associated with B symptoms, Ann Arbor stage, lymphocyte count and the level of lactate dehydrogenase (P <0.05), while the expression level of Hes1 was significantly higher in patients with B symptoms (P <0.05). Notch+/Hes1+ expression was found in 21 DLBCL tissues (38.9%), and there was a correlation between Notch1 and Hes1 expression (r =0.296, P <0.05). Bioinformatics analysis (Oncomine database) showed that the mRNA expressions of Notch1 and Hes1 in the Brune dataset were significantly higher than those in the control tissues (P <0.05). CONCLUSION: The expressions of Notch1 and Hes1 in DLBCL are significantly higher than those in lymphadenitis, and correlated with B symptoms and Ann Arbor stage, suggesting that Notch1 and Hes1 play important roles in the occurrence and development of DLBCL.

Dysregulated Gln-Glu-α-ketoglutarate axis impairs maternal decidualization and increases the risk of recurrent spontaneous miscarriage.

Recurrent spontaneous miscarriage (RSM) affects 1%-2% of fertile women worldwide and poses a risk of future pregnancy complications. Increasing evidence has indicated that defective endometrial stromal decidualization is a potential cause of RSM. Here, we perform liquid chromatography with mass spectrometry (LC-MS)-based metabolite profiling in human endometrial stromal cells (ESCs) and differentiated ESCs (DESCs) and find that accumulated α-ketoglutarate (αKG) derived from activated glutaminolysis contributes to maternal decidualization. Contrarily, ESCs obtained from patients with RSM show glutaminolysis blockade and aberrant decidualization. We further find that enhanced Gln-Glu-αKG flux decreases histone methylation and supports ATP production during decidualization. In vivo, feeding mice a Glu-free diet leads to a reduction of αKG, impaired decidualization, and an increase of fetal loss rate. Isotopic tracing approaches demonstrate Gln-dependent oxidative metabolism as a prevalent direction during decidualization. Our results demonstrate an essential prerequisite of Gln-Glu-αKG flux to regulate maternal decidualization, suggesting αKG supplementation as a putative strategy to rectify deficient decidualization in patients with RSM.

Risk factors of temperature increase after cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy.

Background: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the standard treatment for patients with peritoneal cancer (PC). Following CRS-HIPEC, patients may also face risks caused by whole body hyperthermia. This study analyzed the incidence of temperature increases following CRS-HIPEC and identified the attendant risk factors. Methods: A retrospective analysis was carried out among 458 patients who received CRS-HIPEC at the Fourth Hospital of Hebei Medical University between August 2018 and January 2021. The patients were divided into two groups according to post-HIPEC axillary temperature (≥38°C), with the demographics and the laboratory test results subsequently analyzed and compared, and the risk factors pertaining to temperature increases analyzed using univariate and multivariate logistic regression. Results: During CRS-HIPEC, 32.5% (149/458) of the patients with a temperature increase had an axillary temperature of not lower than 38°C, and 8.5% (39/458) of the patients with hyperpyrexia had an axillary temperature of not lower than 39°C. Female gender, gynecological malignancies, type of chemotherapy drug, increased postoperative neutrophil percentage, and a sharp drop in postoperative prealbumin were associated with the incidence of a temperature increase and axillary temperatures of >38°C. Among these factors, the type of chemotherapy drug was identified as an independent risk factor for a temperature increase during CRS-HIPEC. Conclusion: By determining the risk factors pertaining to temperature increases during CRS-HIPEC, medical staff can identify the attendant risks among the patients and thus take preventive measures in a timely manner to maintain the patient's body temperature at a stable level. This suggests that further clinical research should be conducted to build a risk-prediction model for temperature increases following CRS-HIPEC.

Photo-Driven Iron-Induced Non-Oxidative Coupling of Methane to Ethane.

Photo-driven CH4 conversion to multi-carbon products and H2 is attractive but challenging, and the development of efficient catalytic systems is critical. Herein, we construct a solar-energy-driven redox cycle for combining CH4 conversion and H2 production using iron ions. A photo-driven iron-induced reaction system was developed, which is efficient at selective coupling of CH4 as well as conversion of benzene and cyclohexane under mild conditions. For CH4 conversion, 94 % C2 selectivity and a C2 H6 formation rate of 8.4 µmol h-1 is achieved. Mechanistic studies reveal that CH4 coupling is induced by hydroxyl radical, which is generated by photo-driven intermolecular charge migration of an Fe3+ complex. The delicate coordination structure of the [Fe(H2 O)5 OH]2+ complex ensures selective C-H bond activation and C-C coupling of CH4 . The produced Fe2+ can be used to reduce the potential for electrolytic H2 production, and then turns back into Fe3+ , forming an energy-saving and sustainable recyclable system.

Baseline white matter function predicts short-term treatment response in first-episode schizophrenia.

BACKGROUND AND PURPOSE: The detection and characterization of functional activities in the gray matter of schizophrenia (SZ) have been widely explored. However, the relationship between resting-state functional signals in the white matter of first-episode SZ and short-term treatment response remains unclear. METHODS: Thirty-six patients with first-episode SZ and 44 matched healthy controls were recruited in this study. Patients were classified as nonresponders and responders based on response to antipsychotic medication during a single hospitalization. The fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) of white matter were calculated. The relationships between functional changes and clinical features were analyzed. In addition, voxel-based morphometry was performed to analyze the white matter volume. RESULTS: One-way analysis of variance showed significant differences of fALFF and ReHo in the left posterior thalamic radiation and left cingulum (hippocampus) in the patient group, and the areas were regarded as seeds. The FC was calculated between seeds and other white matter networks. Compared with responders, nonresponders showed significantly increased FC between the left cingulum (hippocampus) and left posterior thalamic radiation, splenium of corpus callosum, and left tapetum, and were associated with the changes of clinical assessment. However, there was no difference in white matter volume between groups. CONCLUSION: Our work provides a novel insight that psycho-neuroimaging-based white matter function holds promise for influencing the clinical diagnosis and treatment of SZ.

A nomogram prediction of citrate reaction during mononuclear cell collection in solid tumor patients.

PURPOSE: Citrate reaction is one of the main adverse events in peripheral blood mononuclear cell (MNC) collection. The aim of this study was to elucidate the risk factors for citrate reaction in patients with advanced solid tumor collection and to construct a nomogram to predict the risk. METHODS: One hundred forty-eight patients with advanced solid tumor who underwent peripheral blood MNC collection in our hospital between January 2021 to December 2021 were selected. The general data, creatinine level before collection, Ca2+ concentration before collection, absolute value of monocyte lymphocytes before collection, circulating blood volume, anticoagulant dosage, and blood collection duration were included in Logistic regression analysis to identify the risk factors of citrate reaction. According to the results of the multivariate logistic model, nomogram was established and receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of the model. RESULTS: Among the 148 solid tumor patients, 35 patients (23.6%) of the 148 patients developed citrate reaction. Multivariate analysis showed that the risk factors for citrate reaction in the process of collection included sex (odds ratio [OR] = 6.718; 95% confidence interval [95% CI]: 2.191-20.594, P = .001), age (OR = 0.957; 95% CI: 0.921-0.996, P = .03), and processed circulating blood volume (OR = 1.001; 95% CI: 1.000-1.002, P = .01). Logistic regression can analyze independent risk factors and establish risk prediction model. The predictive performance of the model is good, and the area under ROC curve is 0.799. CONCLUSIONS: The MNC collection process is safe. The incidence of citrate reaction in the collection of peripheral blood MNCs from patients with advanced solid tumor is related to the age, gender, and processed circulating blood volume of patients. The nomogram can be used to assess a patient's risk of citrate reaction.

Pivotal biological processes and proteins for selenite reduction and methylation in Ganoderma lucidum.

Microbial transformations, especially the reduction and methylation of Se oxyanion, have gained significance in recent years as effective detoxification methods. Ganoderma lucidum is a typical Se enrichment resource that can reduce selenite to elemental Se and volatile Se metabolites under high selenite conditions. However, the detailed biological processes and reduction mechanisms are unclear. In this study, G. lucidum reduced selenite to elemental Se and further aggregated it into Se nanoparticles with a diameter of < 200 nm, simultaneously accompanied by the production of pungent, odorous, and volatile methyl-selenium metabolites. Tandem mass tag-based quantitative proteomic analysis revealed thioredoxin 1, thioredoxin reductase (NADPH), glutathione reductase, 5-methyltetrahydropteroyltriglutamate-homocysteine methyltransferase, and cystathionine gamma-lyase as proteins involved in selenite reduction and methylation. Furthermore, the high expression of proteins associated with cell structures that prompted cell lysis may have facilitated Se release. The upregulation of proteins involved in the defense reactions was also detected, reflecting their roles in the self-defense mechanism. This study provides novel insights into the vital role of G. lucidum in mediating Se transformation in the biogeochemical Se cycle and contributes to the application of fungi in Se bioremediation.

Development of a Cancer-Associated Fibroblast-Related Prognostic Model in Breast Cancer via Bulk and Single-Cell RNA Sequencing.

Background: The most numerous cells in the tumor microenvironment, cancer-associated fibroblasts (CAFs) play a crucial role in cancer development. Our objective was to develop a cancer-associated fibroblast breast cancer predictive model. Methods: We acquire breast cancer (BC) scRNA-seq data from Gene Expression Omnibus (GEO), and "Seurat" was used for data processing, including quality control, filtering, principal component analysis, and t-SNE. Afterward, "singleR" software was used to annotate cells. Seurat's "FindAllMarkers" program is used to locate particular CAF markers. clusterProfiler was used to analyze Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The Cancer Genome Atlas (TCGA) database was utilized to provide univariate Cox regression, least absolute shrinkage operator (LASSO) analysis using bulk RNA-seq data. For model development, multivariate Cox regression studies are used. Utilizing pRRophetic and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms, chemosensitivity and immunotherapy response were predicted. The "rms" software was used to facilitate and simplify modeling. Results: Integrating the scRNA-seq (GSE176078) dataset yielded 28 cell clusters. In addition, well-known cell types helped identify 12 cell types. We found 193 marker genes that are elevated in CAFs. In addition, a five-gene predictive model associated to CAF was created in the training set. In the training set, the validation set, and the external validation set, greater risk scores were associated with a worse prognosis. And individuals with a higher risk score were more susceptible to immunotherapy and conventional chemotherapy medicines. Conclusion: In conclusion, we establish a strong prognostic model comprised of 5 genes related with CAF that might serve as a potent prognostic indicator and aid clinicians in making more rational medication choices.

i-CRISPR: a personalized cancer therapy strategy through cutting cancer-specific mutations.

Developing a strategy to specifically kill cancer cells without inducing obvious damage to normal cells may be of great clinical significance for cancer treatment. In the present study, we developed a new precise personalized strategy named "i-CRISPR" for cancer treatment through adding DNA damage repair inhibitors(i) and inducing cancer cell-specific DNA double strand breaks by CRISPR. Through in vitro and in vivo experiments, we confirmed the efficacy of this strategy in multiple cancer models and revealed the mechanism of cell death. Our strategy might provide a novel concept for precise cancer therapy.

Adipose-Derived Stem Cells Exosomes Improve Fat Graft Survival by Promoting Prolipogenetic Abilities through Wnt/ß-Catenin Pathway.

Autologous fat grafting has been widely used in plastic surgery in recent years, but the unstable retention of fat graft has always been a key clinical problem. Adipose tissue has poor tolerant to ischemia, so the transplanted adipose tissue needs to rebuild blood supply at an early stage in order to survive stably. Our previous study has found that comparing to human foreskin fibroblast exosome (HFF-Exo), human adipose-derived stem cells exosome (hADSC-Exo) can significantly improve the proliferation of vascular endothelial cells and the angiogenic effect of artificial dermal preconstructed flaps. Therefore, the ability of hADSC-Exo to improve the retention of adipose grafts and its potential regenerative mechanism aroused our strong interest. In this study, we applied hADSC-Exo and HFF-Exo to adipose grafts and explored the potential regeneration mechanism through various means such as bioinformatics, immunofluorescence, immunohistochemistry, and adipogenic differentiation. The results showed that hADSC-Exo can significantly promote grafts angiogenesis and adipogenic differentiation of ADSC to improve the retention of fat grafts and may downregulate the Wnt/ß-catenin signaling pathway to promote the adipogenic differentiation. In summary, our results provide a theoretical basis for the clinical translation of hADSC-Exo in fat grafting.